Several recent developments have instilled new hope for the establishment of effective prevention and treatment strategies for insulin depedent diabetes mellitus (IDDM): 1) Advances made in the understanding of regulatory T cell function, 2) New knowledge of the role the CTLA-4 costimulation molecule has in the down-modulation of T cell function and tolerance induction 3) the powerful therapeutic potential of islet cell transplantation 4) the possibility for the unlimited availability of islet cells from xenogeneic sources or from manipulations of allogeneic stem cell lines. A combination of these strategies, along with a clear understanding of beta cell physiology might eventually provide the required therapeutic tools for the treatment of IDDM and for its ultimate prevention. At this time, the islet cell transplantation provides a powerful alternative to a lifetime of insulin therapy. Unfortunately, the utility of islet cell transplants is limited due to graft rejection, toxicity and the global immunosuppression associated with many of the current immunosuppressive therapies. Tolerization of islet specific autoreactive T cells will help to prevent IDDM and/or restore islet cell function. Therefore, it is imperative to develop new modal/ties of treatment that selectively inhibit allo-, xeno- or autoimmune responses directed against islets with little or no effect on the global immune responses. In our previous work, we showed that a bispecific antibody (BiAb), consisting of anti-TSHR and anti-CTLA-4 antibodies can deliver anti-CTLA-4 to either cells or tissue (thyroid), that express TSHR and induce tissue-specific tolerance and prevent the development of autoimmune thyroiditis. In this application, under aim 1, we propose to test the potential of an anti-alloantigen (anti-H2d)/anti-CTLA-4 BiAb to induce allospecific immune tolerance upon islet transplantation. Under aim 2, we will test the specificity and mechanism of T cell modulation initiated by the BiAb. Under aim 3: we will prepare a new BiAb using an islet cell specific antibody and anti-CTLA-4 antibody to test ability to prevent and treat Type I DM in a murine model of spontaneous diabetes.